Obesity is excess body weight for a particular age, sex and height as a consequence of imbalance between energy intake and energy expenditure. The primary causes of obesity are either due to overeating, inadequate exercise or eating disorder, some genetic disorders, underlying illness (e.g., hypothyroidism), certain medications, sedentary lifestyle, a high glycemic diet (i.e., a diet that consists of meals that give high post prandial blood sugar) weight cycling (caused by repeated attempts to lose weight by dieting, eating disorders), stress and insufficient sleep.
During the past 20 years, obesity among adults has risen significantly in the United States. The latest data from the National Center for Health Statistics show that 30 percent of U.S. adults of 20 years of age and older, i.e. over 60 million people, are obese. The percentage of young people, who are overweight, has more than tripled since 1980. More than 16% of the children and teens aged 6-19 years, that is over 9 million young people, are considered overweight.
Although, the US national health objectives for the year 2010 is to reduce the prevalence of obesity to less than 15% among adults, current data indicate that the situation is worsening rather than improving (http://www.cdc.gov/nchs/products/pubs/pubd/hestats/overweight/overwght_adult_03.htm). Obesity increases the risk of many diseases and health conditions such as hypertension, dyslipidemia (for example, high total cholesterol or high levels of triglycerides), type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep disorders, respiratory problems, tumors (endometrial, breast, and colon), arteriosclerosis and heart failure.
As per World Health Organisation's latest projections, approximately 1.6 billion adults (age 15+) were overweight and at least 400 million adults were obese globally in 2005. WHO further projects that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese (WHO's fact sheet No. 311, September 2006, http://www.who.int/mediacentre/factsheets/fs311/en/index.html). Obesity in Europe was recognized as a serious problem, with up to 27% of men, 38% of women and 3 million children are clinically obese (http://ec.europa.eu/health/ph_determinants/life_style/nutrition/green_papemutritiongp_co183_en.pdf). The obesity was not limited to developed countries, but it was rapidly becoming a problem in developing countries as well. The number of those affected, particularly children, are continuing to increase at an alarming rate. Obesity is already responsible for 2-8% of health care costs and 10-13% of deaths in different parts of Europe (http://www.euro.who.int/obesity). Recent studies have shown that approximately a third of variance in adult body weights result from genetic influences. Leptin, an adipocyte and placenta-derived circulating protein, regulates the magnitude of fat stores in the body leading to obesity. Gastrointestinal peptides, neurotransmitters and adipose tissue may also have an etiologic role in obesity. Obesity and adipose tissue expansion increase the risk of hypertension, type 2 diabetes, arthritis, elevated cholesterol, cancer and serious hormonal imbalances in women, leading to sterility. Low caloric diets with or without exercise can help with temporary weight loss; however, diet and exercise alone have not proven successful for long-term solutions in weight management (H. G. Preuss, et al, Nutrition Research, 2004, 24, 45-48). In addition, supplementation with drugs that suppress appetite, reduce food intake, reduce dietary fat absorption, increase energy expenditure and effect nutrient partitioning or metabolism have potential efficacy but they are unfortunately accompanied by adverse side effects (C. A. Haller and N. L. Benowitz. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids (New England J. Medicine, 2000, 343, 1833-1838). Herbal and natural products containing Gymnema extract, Garcinia extract, or carnitine are known to prevent fat accumulation through the inhibition of fat absorption, enhancement of fat decomposition, and the enhancement of fat consumption by the body.
Ever since obesity has become an epidemic, the word “diet” is gathering lot of interest from different sections of many people. Many methods for weight reduction have been introduced, which leads to disproportion of nourishment and abnormal body metabolism.
Obesity is the culmination of many underlying mechanisms. Obesity is characterized as uncontrolled adipose tissue mass in the body and recognized as the fastest growing metabolic disorder in the world. An increase in adipose tissue can be the result of the production of new fat cells through the process of adipogenesis and/or the deposition of increased amounts of cytoplasmic triglyceride or lipid droplets per cell. In the adipogenesis process, proliferation of preadipocytes or precursor fat cells needs to be followed by the differentiation of these cells to the mature adipocyte phenotype. Increased lipid accumulation in the mature adipocyte cells is the most important feature of obesity disorder. Peroxisome Proliferator-Activator Receptor gamma (PPAR-γ) is predominantly expressed in adipocytes and is a key determination factor for adipogenesis.
Fat is stored as triglycerides form in adipose tissue. The breakdown of this fat in fat cells into glycerol and fatty acids is known as lipolysis. During this process, free fatty acids are released into the bloodstream and circulate throughout the body. The hormones called epinephrine, norepinephrine, glucagon and adrenocorticotropic hormone induce lipolysis. These hormones trigger 7TM receptors, which activate adenylate cyclase. This results in increased production of cAMP, which activates protein kinase A, which subsequently activate lipases found in adipose tissue. It is known that PPAR alpha plays an important role in regulating lipolysis through the control of lipid metabolic enzymes such as lipoprotein lipase (LPL) Ziuozenkova et al., PNAS, Mar. 4, 2003, Vol. 100 no. 5, 27302735).
Inhibition of the differentiation of pre-adipocytes into mature adipocytes leads to the reduction of new adipose tissue and reduction in the formation of fat reserves. Modulation of adipogenesis and lipolysis in humans may thus lead to reduction in the burden of obesity. The body's adrenergic system plays a major part in regulating energy expenditure and lipolysis. In this process catecholamines mobilize energy-rich lipids by stimulating lipolysis in fat cells and thermogenesis in brown adipose tissue and skeletal muscle. The adrenergic receptor β3 is the principal receptor mediating catecholamine-stimulated thermogenesis in brown adipose tissue, which in humans is distributed about the great vessels in the thorax and abdomen (Thomas, G N, International Journal of Obesity, 545-551, 24, 2000). The β3-adrenergic receptor is also important in mediating the stimulation of lipolysis by catecholamines in the white fat cells of several species, including humans. The brown adipose tissue differs from white adipose tissue in that it has large numbers of mitochondria containing a so-called uncoupling protein, which can stimulate oxidative phosphorylation and thereby increase the metabolic rate (Peter Arner, The β3-Adrenergic Receptor—A Cause and Cure of Obesity? The New England Journal of Medicine, 333: p 382-383). The role of brown adipose tissue is to oxidize lipids to produce heat and rid the body of excess fat. White adipose tissue, which includes subcutaneous and visceral adipose tissue, is much more abundant. It serves to store fat, which can be mobilized by lipolysis to generate free fatty acids for use by other tissues.
Selective agonists of β3-adrenergic receptors are potentially useful in treating obesity because they could enhance energy expenditure with few β1- or β2-adrenergic side effects. A number of β3-adrenergic agonists have been developed and tested experimentally. Hence the treatment with β3-selective agonists can markedly increase energy expenditure and decreases body weight and obesity.
There are a few therapeutic interventions based on pharmaceutical drugs, such as phentermine (Fastin, Adipex P), for weight control but these methods exhibit side effects like high blood pressure, headache, insomnia, irritability and nervousness. The other important drug therapy for weight control is Xenical (Roche Pharm. Co. Ltd., Swiss), Reductil (Abbot Co. Ltd., USA). The most common side effects are gas, cramps and diarrhea, elevated blood pressure. All these therapies are based on active ingredients that are of synthetic origin. Effective anti-obese therapies with satisfactory efficacy and acceptable safety have not been developed so far.
More importantly, anti-obese agents of natural origin with proven safety are of great demand to control this growing menace. It is particularly advantageous for inhibition, amelioration and prevention of obesity if an anti-obesity action can be imparted to food products and beverages, which are ordinarily ingested.
Hence, presently there is great demand for development of agents for prevention, maintenance and remedy of obesity, which are safe and effective. The major emphasis now for many organizations around the globe has been to develop new dietary ingredients and compositions especially from natural origin.
Holoptelea integrifolia is a tall tree distributed through out India, but more densely in Gujarat, Madhya Pradesh, Hardwar and in the Himalayas. It belong to Ulmaceae family and is known by many local names, but more popularly as Kanju, Papri, nemali etc. Holoptelea integrifolia seed oil is a good source of edible oil. Its leaves are commonly used along with a blend of other Ayurvedic herbs in herbal tea preparations for detoxification and rejuvenation. This herbal tea is also known to clear cellulite deposits and obliterates stretch marks that are fall out of a weight problem. Holoptelea integrifolia was shown to exhibit antiviral activity in vitro assays. It was recognized as one of the plant species useful to control air pollution.
However, none of the prior art reported or disclosed the application of the extracts of Holoptelea integrifolia plant or purified fractions developed therefrom for the amelioration of adipogenesis and lipolysis or the prevention or treatment or maintenance adipogenesis and/or lipolysis mediated disorders such as obesity.